This invention relates to novel aminopyrazole derivatives or salts thereof. More particularly, it relates to aminopyrazole derivatives represented by the following formula, or salts thereof. 
wherein:
X1 and X2 each independently represent a hydrogen atom or a halogen atom, or when X1 and X2 are attached to positions adjacent to each other, they may be united together to form a lower alkylenedioxy group;
Q represents a pyridyl group or a quinolyl group;
R1 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted aryl group;
R2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group in which the aryl moiety may optionally be substituted;
R3 represents a hydrogen atom, an organic sulfonyl group, or xe2x80x94C(xe2x95x90Y)xe2x80x94R4 in which R4 is a hydrogen atom or an organic residue and Y is an oxygen or sulfur atom;
provided that, when R3 is a hydrogen atom, R1 is a group other than a hydrogen atom and R2 is a hydrogen atom.
TNF-xcex1, IL-1, IL-6 and COX-II are proteins which are predominantly produced by immunocompetent cells such as macrophages and neutrophilic leukocytes, and constitute important factors participating, for example, in immunoregulatory functions and inflammatory symptoms. TNF-xcex1 and the like are also known as factors participating in many biological reactions in the hematopoietic system, the endocrine system, the nervous system and the like. Accordingly, the excessive or uncontrolled production of TNF-xcex1 and the like in the living body are believed to be closely related to the onset and aggravation of diseases associated with TNF-xcex1 and the like.
On the other hand, p38MAP kinase found within various types of cells in the living body are known to activate, in particular, some types of transcription factors. Specifically, transcription factors such as NF-xcexaB, AP-1 and CREB bind to a certain DNA sequence common to TNF-xcex1, IL-1, IL-6, COX-II and the like, and thereby promote transcription. Within the cell nucleus, these transcription factors are activated by the action of p38MAP kinase, so that proteins such as TNF-xcex1 are synthesized from the transcribed mRNA The mRNA which has gone out of the nucleus in the presence of calcium is inactivated by binding to a protein having a specific sequence, and decomposed rapidly. However, in the presence of p38MAP kinase activated by phosphorylation, the mRNA is released from the protein and thereby activated. Consequently, it is believed that the synthesis of proteins such as TNF-xcex1, IL-1, IL-6 and COX-II is also promoted along this pathway.
Accordingly, it is believed that the production of TNF-xcex1, IL-1, IL-6, COX-II and the like can be hindered by inhibiting p38MAP kinase. On the basis of this concept, there have been proposed a number of compounds which have a p38MAP kinase inhibiting activity and thereby hinder the production of TNF-xcex1, IL-1, IL-6, COX-II and the like (see, for example, Bioorganic and Medicinal Chemistry, Vol. 5, No. 1, pp. 49-64, 1997; and Japanese Patent Laid-Open No. 503017/""95).
It is expected that these TNF-xcex1, IL-1, IL-6 or COX-II production inhibitors will be effective in the treatment or prevention of diseases associated with TNF-xcex1, IL-1, IL-6 or COX-II, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, viral and bacterial infections, asthma, septic shock, IBD, Crohn""s disease, Alzheimer""s disease, diabetes, cachexia, osteoporosis, graft versus host disease, adult RDS, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, SLE, thrombosis, born resorption disease, chronic pulmonary inflammation disease, cardiac reperfusion injury, renal reperfusion injury, cancer, Reiter""s syndrome, preterm labor, eczema, allograft rejection, stroke, fever, Behxc3xa7et""s disease, neuralgia, meningitis, sunburn, contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, pancreatitis, glioblastoma, bleeding, joint inflammation, endotoxic shock, parasitic infections, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, IBS, transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling, low back pain, laryngopharyngitis, Kawasaki disease, myelopathy and atopic dermatitis.
Meanwhile, as to aminopyrazole derivatives, there have been known some aminopyrazole derivatives in which the 3- or 5-position of the pyrazole ring is substituted by a pyridyl group or an optionally substituted amino group, the 5- or 3-position is substituted by a pyridyl group, and the 4-position is substituted by a pyridyl group or an optionally substituted phenyl group (Japanese Patent Laid-Open No. 17470/""93). However, neither description nor suggestion is found therein about their p38MAP kinase inhibiting activities.
Very recently, certain aminopyrazole derivatives having p38MAP kinase inhibiting activities have been proposed (see the pamphlets of PCT International Publications WO98/52940 and WO98/52941).
The present inventors have now found that aminopyrazole derivatives in which one of the 3- and 5-positions of the pyrazole ring is substituted by an optionally substituted amino group, the other of the 3- and 5-positions thereof is substituted by a phenyl group that may be substituted by a halogen atom or a lower alkylenedioxy group, and the 4-position thereof is substituted by a pyridyl or quinolyl group have excellent p38MAP kinase inhibiting activities and are hence effective in hindering the production of TNF-xcex1, IL-1, IL-6, COX-II and the like.
Thus, the present invention provides aminopyrazole derivatives represented by the above formula (I), or salts thereof
The term xe2x80x9clowerxe2x80x9d as used herein means that the group or compound modified by this term has 6 or less carbon atoms and preferably 4 or less carbon atoms.
Thus, examples of the xe2x80x9clower alkyl groupxe2x80x9d include methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl sec-butyl, t-butyl, n-pentyl and n-hexyl, and examples of the xe2x80x9clower alkylenedioxy groupxe2x80x9d include methylenedioxy, ethylenedioxy and propylenedioxy.
The xe2x80x9caryl groupxe2x80x9d or the aryl moiety of the xe2x80x9caralkyl groupxe2x80x9d may be a monocyclic or polycyclic aromatic ring, and examples thereof include phenyl and naphthyl.
The xe2x80x9corganic sulfonyl groupxe2x80x9d is a residue obtained by eliminating a hydroxyl group from an organic sulfonic acid, and examples thereof include methanesulfonyl ethanesulfonyl, benzenesulfonyl and p-toluenesulfonyl. On the other hand, the term xe2x80x9chalogen atomxe2x80x9d comprehends fluorine, chlorine, bromine and iodine atoms.
The xe2x80x9cpyridyl group or quinolyl groupxe2x80x9d represented by the symbol Q may preferably be a 4-pyridyl group or a 4-quinolyl group.
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted lower alkyl groupxe2x80x9d represented by the symbol R1 include, for example, halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, aralkyloxy, amino, lower alkylamino, di(lower alkyl)amino, aralkyloxycarbonylamino and lower alkoxycarbonylamino. The lower alkyl group may be substituted by one or two substituents selected from the foregoing. The substituents which can be present in the xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d represented by the symbol R1 include, for example, halogen, lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkoxycarbonylamino and nitro. The aryl group may be substituted by one or two substituents selected from the foregoing.
The substituents which can be present in the aryl moiety of the xe2x80x9caralkyl group in which the aryl moiety may optionally be substitutedxe2x80x9d represented by the symbol R2 may be the same as described above for the substituent(s) present in the aryl group represented by the symbol R1.
The xe2x80x9corganic residuexe2x80x9d represented by the symbol R4 may be any residue derived from an organic compound without any particular limitation. As used herein, however, the term xe2x80x9corganic residuexe2x80x9d generally comprehends substituted or unsubstituted, saturated or unsaturated straight-chain, branched or cyclic hydrocarbon radicals, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted amino groups, and substituted carbonyl groups.
The xe2x80x9csubstituted or unsubstituted, saturated or unsaturated straight-chain, branched or cyclic hydrocarbon radicalsxe2x80x9d preferably include substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted cycloalkenyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted bridged cycloalkyl groups, and substituted or unsubstituted spiroalkyl groups. More preferably, they include substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, and substituted or unsubstituted aryl groups. Among them, substituted or unsubstituted lower alkyl groups are especially preferred.
As used herein, the term xe2x80x9calkyl groupxe2x80x9d generally comprehends straight-chain or branched alkyl groups having 1 to 20 carbon atoms. Examples thereof include, in addition to the above-described lower alkyl groups, 5-methylhexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl and n-octadecyl. The term xe2x80x9calkenyl groupxe2x80x9d generally comprehends straight-chain or branched alkenyl groups having 2 to 20 carbon atoms, and examples thereof include vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 1,4-hexadienyl and 9-octadecenyl. The term xe2x80x9calkynyl groupxe2x80x9d generally comprehends straight-chain or branched alkynyl groups having 2 to 20 carbon atoms, and examples thereof include ethynyl, 2-propynyl and 4-pentynyl. The term xe2x80x9ccycloalkyl groupxe2x80x9d generally comprehends cycloalkyl groups having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term xe2x80x9ccycloalkenyl groupxe2x80x9d generally comprehends cycloalkenyl groups having 4 to 10 carbon atoms, and examples thereof include 2-cyclobutenyl, 2-cyclopentenyl and 2-cyclohexenyl. The term xe2x80x9caryl groupxe2x80x9d generally comprehends monocyclic or polycyclic aryl groups having 6 to 20 carbon atoms, and examples thereof include phenyl, 1-indenyl, 1-naphthyl, 2-naphthyl, 1-azulenyl, 2-anthryl, 2-phenanthryl and 1-acenaphthenyl. Moreover, the term xe2x80x9cbridged cycloalkyl groupxe2x80x9d generally comprehends bridged cycloalkyl groups having 4 to 20 carbon atoms, and examples thereof include bicyclo[2.2.1]hept-2-yl, bicyclo[3.2.1]oct-2-yl, bicyclo[4.3.2]undec-2-yl and adamantyl. The term xe2x80x9cspiroalkyl groupxe2x80x9d generally comprehends spiroalkyl groups having 7 to 20 carbon atoms, and examples thereof include spiro[4.5]dec-2-yl and spiro[5.5]dec-3-yl.
The heterocyclic group present in the xe2x80x9csubstituted or unsubstituted heterocyclic groupxe2x80x9d used herein may preferably be a monocyclic or polycyclic, saturated or partially saturated, or aromatic heterocycle which contains 1 to 4 heteroatoms selected from N, O and S and has a four- to eight-membered ring. Alternatively, the heterocycle may further be fused with a cyclic hydrocarbon to form a fused ring. Among such heterocyclic groups, more preferred ones are monocyclic or bicyclic, saturated or aromatic heterocyclic groups which contain 1 or 2 heteroatoms selected from N, O and S and have a five- or six-membered ring, and which may optionally be fused with a phenyl group.
Thus, these xe2x80x9cheterocyclic groupsxe2x80x9d include, for example, monocyclic heteroaryl groups such as pyrrolyl, furyl, thienyl imidazolyl, pyrazolyl, oxazolyl isoxazolyl thiazolyl triazolyl, thiadiazolyl, tetrazolyl pyridyl, pyranyl pyrimidinyl pyridazinyl, pyrazinyl azepinyl and azocinyl polycyclic heteroaryl groups such as purinyl naphthidinyl and pteridinyl; heteroaryl groups fused with a cyclic hydrocarbon radical to form a fused ring, such as benzothienyl benzofuranyl indolyl isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl quinolyl isoquinolyl, chromenyl phthalazinyl quinazolinyl quinoxalinyl carbazolyl phenanthridinyl, acridinyl and dibenzazepinyl; saturated heterocyclic groups such as azetidinyl pyrrolidinyl, tetrahydrofuranyl piperidinyl, piperazinyl and morpholinyl; and partially saturated heterocyclic groups fused with a cyclic hydrocarbon radical to form a fused ring, such as indolinyl isoindolinyl 1,2,3,4-tetrahydroisoquinolyl chromanyl and isochromanyl.
Moreover, the xe2x80x9csubstituted or unsubstituted amino groupsxe2x80x9d used in the definition of the aforesaid xe2x80x9corganic residuexe2x80x9d include, for example, lower alkylamino groups, di(lower alkyl)amino groups, and substituted or unsubstituted arylamino groups, in addition to the unsubstituted amino group. Among them, substituted or unsubstituted arylamino groups are preferred.
The term xe2x80x9csubstituted carbonyl groupsxe2x80x9d used in the definition of the aforesaid xe2x80x9corganic residuexe2x80x9d means carbonyl groups substituted by an organic group. Preferred examples thereof include substituted or unsubstituted alkyloxycarbonyl groups, substituted or unsubstituted alkylcarbonyl groups, and substituted or unsubstituted arylcarbonyl groups. Among them, substituted or unsubstituted lower alkyloxycarbonyl groups and substituted or unsubstituted phenylcarbonyl groups are more preferred.
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted alkyl groupsxe2x80x9d used in the definition of the organic residue include, for example, halogen, hydroxyl lower alkoxy, lower alkanoyloxy, arylcarbonyloxy, aryloxy, mercapto, lower alkylthio, lower alkanoylthio, arylcarbonylthio, arylthio, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, arylcarbonylamino, aralkyloxycarbonylamino, lower alkoxycarbonylamino, N-(lower alkyl)-N-(lower alkoxycarbonyl)amino, guanidino, carboxyl, lower alkoxycarbonyl, aralkyloxycarbonyl, carbamoyl, lower alkylcarbonyl, arylcarbonyl, cycloalkyl aryl [this aryl may optionally be substituted by 1 to 5 substituents selected from halogen, lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, aralkyloxycarbonylamino, lower alkoxycarbonylamino and nitro], and monocyclic or bicyclic heterocyclic groups which contain 1 or 2 heteroatoms selected from N, S and O and have a five- or six-membered ring and which may further be fused with a benzene ring (these heterocyclic groups may optionally be substituted by 1 or 2 substituents selected from halogen, lower alkyl, lower alkoxy and nitro). The alkyl group may be substituted by 1 to 3 substituents selected from the foregoing ones. Among others, preferred ones are lower alkyl groups which may be substituted by 1 or 2 substituents selected from halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, aryloxy, amino, lower alkylamino, di(lower alkyl)amino, aralkyloxycarbonylamino, lower alkoxycarbonylamino, N-(lower alkyl)-N-(lower alkoxycarbonyl)amino, carboxyl, lower alkoxycarbonyl, lower cycloalkyl, aryl [this aryl may optionally be substituted by 1 to 5 halogen atoms, or 1 to 3 substituents selected from lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkoxycarbonylamino and nitro], and monocyclic or bicyclic heteroaryl groups which contain 1 or 2 heteroatoms selected from N and S and have a five- or six-membered ring and which may further be fused with a benzene ring (these heteroaryl groups may optionally be substituted by a lower alkyl group or groups). Among them, especially preferred ones are lower alkyl groups substituted by an aryl group [this aryl group may optionally be substituted by 1 to 5 halogen atoms, or 1 to 3 substituents selected from lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkylthio, amino and nitro], or a five- or six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and S (this heteroaryl group may optionally be substituted by one lower alkyl group).
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted alkenyl groupsxe2x80x9d used in the definition of the organic residue include, for example, halogen and aryl [this aryl may optionally be substituted by 1 to 5 substituents selected from halogen, lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, aralkyloxycarbonylamino, lower alkoxycarbonylamino and nitro]. The alkenyl group may be substituted by 1 or 2 substituents selected from the foregoing ones. Among them, unsubstituted alkenyl groups having 2 to 4 carbon atoms are especially preferred.
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted cycloalkyl groupsxe2x80x9d used in the definition of the organic residue include, for example, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, carboxyl, lower alkoxycarbonyl and oxo. The cycloalkyl group may be substituted by 1 or 2 substituents selected from the foregoing ones. Among them, unsubstituted cycloalkyl groups having 5 to 7 carbon atoms are especially preferred.
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted aryl groupsxe2x80x9d used in the definition of the organic residue include, for example, halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino and nitro. The aryl group may be substituted by 1 to 3 substituents selected from the foregoing ones. Among them, unsubstituted aryl groups having 6 to 10 carbon atoms are especially preferred.
The substituents which can be present in the xe2x80x9csubstituted or unsubstituted heterocyclic groupsxe2x80x9d used in the definition of the organic residue include, for example, halogen, lower alkyl lower alkoxy, lower alkylenedioxy, hydroxyl, lower alkanoyloxy, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, aralkyloxycarbonyl, lower alkoxycarbonyl and nitro. The heterocyclic group may be substituted by 1 to 3 substituents selected from the foregoing ones. Among them, especially preferred ones are monocyclic or bicyclic heterocyclic groups which contain 1 or 2 heteroatoms selected from N and O and have a five- or six-membered ring, which may optionally be substituted by one aralkyloxycarbonyl group or lower alkoxycarbonyl group, and which may further be fused with a benzene ring.
The xe2x80x9csubstituted or unsubstituted arylamino groupsxe2x80x9d used in the definition of the substituted or unsubstituted amino groups include, for example, arylamino groups in which the aryl moiety may optionally be substituted by 1 to 5 halogen atoms, or 1 to 3 substituents selected from lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, lower alkylthio, amino and nitro.
Furthermore, the xe2x80x9csubstituted or unsubstituted lower alkyloxycarbonyl groupsxe2x80x9d used in the definition of the substituted carbonyl groups include, for example, lower alkyloxycarbonyl groups which may optionally be substituted by 1 or 2 substituents selected from hydroxyl, lower alkoxy, amino, lower alkylamino and aryl [this aryl may optionally be substituted by 1 to 5 substituents selected from halogen, lower alkyl halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkoxycarbonylamino and nitro]. Among them, unsubstituted lower alkyloxycarbonyl groups are especially preferred.
The xe2x80x9csubstituted or unsubstituted phenylcarbonyl groupsxe2x80x9d used in the definition of the substituted carbonyl groups include, for example, phenylcarbonyl groups which may optionally be substituted by 1 to 3 substituents selected from halogen, lower alkyl, lower alkoxy, hydroxyl amino, lower alkoxycarbonylamino and nitro. Among them, unsubstituted phenylcarbonyl groups are especially preferred.
Furthermore, the xe2x80x9caralkyl groupxe2x80x9d as used herein is an alkyl group substituted by an aryl group. Preferred examples thereof include aryl-substituted lower alkyl groups such as benzyl, 1-phenyl-ethyl 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl and diphenylmethyl.
The xe2x80x9clower alkoxy groupxe2x80x9d is a lower alkyloxy group in which the lower alkyl moiety has the above-defined meaning. Examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy.
The xe2x80x9clower alkanoyloxy groupxe2x80x9d is a lower alkylcarbonyloxy group in which the lower alkyl moiety has the above-defined meaning. Examples thereof include acetoxy, propionyloxy, butyryloxy and valeryloxy.
Examples of the xe2x80x9carylcarbonyloxy groupxe2x80x9d include benzoyloxy, 4-nitrobenzoyloxy and 2-naphthoyloxy.
Examples of the xe2x80x9caryloxy groupxe2x80x9d include phenoxy, 4-methylphenoxy and 2-naphthoxy.
Examples of the xe2x80x9caralkyloxy groupxe2x80x9d include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, 1-phenylpropyloxy and 3-phenylpropyloxy.
Examples of the xe2x80x9clower alkylthio groupxe2x80x9d include methylthio, ethylthio and isopropylthio.
Examples of the xe2x80x9clower alkanoylthio groupxe2x80x9d include acetylthio and propionylthio.
Examples of the xe2x80x9carylcarbonylthio groupxe2x80x9d include benzoylthio and 1-naphthoylthio.
Examples of the xe2x80x9carylthio groupxe2x80x9d include phenylthio and 2-naphthylthio.
Examples of the xe2x80x9clower alkylamino groupxe2x80x9d include methylamino, ethylamino and n-propylamino.
Examples of the xe2x80x9cdi(lower alkyl)amino groupxe2x80x9d include dimethylamino, diethylamino and di-n-propylamino.
Examples of the xe2x80x9clower alkanoylamino groupxe2x80x9d include acetylamino and propionylamino.
Examples of the xe2x80x9carylcarbonylamino groupxe2x80x9d include benzoylamino.
Examples of the xe2x80x9caralkyloxycarbonylamino groupxe2x80x9d include benzyloxycarbonylamino, 4-bromobenzyloxycarbonylamino, 4-methoxybenzyloxycarbonylamino and 4-nitrobenzyloxycarbonylamino.
Examples of the xe2x80x9clower alkoxycarbonylamino groupxe2x80x9d include t-butoxycarbonylamino.
Examples of the xe2x80x9cN-(lower alkyl)-N-(lower alkoxy)-carbonylamino groupxe2x80x9d include N-methyl-N-t-butoxycarbonylamino and N-ethyl-N-t-butoxycarbonylamino.
Examples of the xe2x80x9clower alkoxycarbonyl groupxe2x80x9d include methoxycarbonyl ethoxycarbonyl and t-butoxycarbonyl.
Examples of the xe2x80x9caralkyloxycarbonyl groupxe2x80x9d include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
Examples of the xe2x80x9clower alkylcarbonyl groupxe2x80x9d include acetyl and propionyl.
Examples of the xe2x80x9carylcarbonyl groupxe2x80x9d include benzoyl.
Examples of the xe2x80x9chalogenated lower alkyl groupxe2x80x9d include trifluoromethyl 2,2,2-trifluoroethyl and pentafluoroethyl.
One preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which X1 is 4-fluoro and X2 is hydrogen.
Another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which Q is 4-pyridyl.
Still another preferred class of compounds in accordance with the present invention are the compounds of formula () in which R1 is unsubstituted lower alkyl.
A further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R2 is hydrogen or methyl.
A still further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R3 is xe2x80x94C(xe2x95x90Y)xe2x80x94R4 and Y is oxygen.
Where R1 represents a hydrogen atom in the compounds of the above formula (I) in accordance with the present invention, such hydrogen atoms are usually attached to one of the two nitrogen atoms constituting the pyrazole ring, at a certain ratio depending on the reaction conditions and the like. Consequently, the position at which R1 is substituted cannot be specified. Accordingly, the representation of the position of the substituent R1 as used in the chemical structural formula given herein means that, xe2x80x9cwhere R1 represents a hydrogen atom, it is unknown which of the two nitrogen atoms constituting the pyrazole ring R1 is attached to.xe2x80x9d Where R1 represents a group other than a hydrogen atom, the position at which R1 is substituted can be specified. Accordingly, the above-described representation means that xe2x80x9cwhere R1 represents a group other than a hydrogen atom, R1 is attached to a fixed one of the two nitrogen atoms constituting the pyrazole ring.xe2x80x9d
In the notation of compounds in the examples and elsewhere, they are represented in such a way that, when R1 is a hydrogen atom, the amino group which may be substituted is attached to the 3-position of the pyrazole ring.
In addition to the compounds described in the examples which will be given later, typical examples of the compounds of the above formula (I) which are provided by the present invention include:
5-(4-fluorophenyl)-3-methanesulfonylamino-4-(4-pyridyl)pyrazole,
5-(3-chloro-4-fluorophenyl)-3-(4-methylbenzenesulfonylamino)-4-(4-pyridyl)pyrazole,
3-acetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-isobutyrylamino-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-methyl-4-(4-pyridyl)-5-(3-trifluoroacetylamino)pyrazole,
3-(3-chloropropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-hydroxyacetylamino-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(3-hydroxypropionylamino)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-methoxyacetylamino-1-methyl-4-(4-pyridyl)pyrazole,
3-ethoxyacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-acetoxyacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-benzoyloxyacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-phenoxyacetylamino-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-mercaptoacetylamino-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-methylthioacetylamino-4-(4-pyridyl)pyrazole,
3-acetylthioacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-benzoylthioacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-phenylthioacetylamino-4-(4-pyridyl)pyrazole,
5-aminoacetylamino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(3-aminopropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(L-leucylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-methylamnioacetylamio-4-(4-pyridyl)pyrazole,
5-diethylaminoacetylamino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-acetylaminoacetylamino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-benzoylaminoacetylamino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(Nxe2x80x2-p-methoxycarbobenzoxy-L-alanylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(Nxe2x80x2-carbo-t-butoxy-glycylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-L-arginylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(3-carboxypropionylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(3-t-butoxycarbonylpropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(3-benzyloxycarbonylpropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(3-carbamoylpropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(3-acetylpropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(3-benzoylpropionylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-cyclopentylacetylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-cyclohexylacetylamino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(4-phenylbutyrylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(2-fluorophenylacetylamino)-4-(4-pyridyl)pyrazole,
3-(4-acetoxyphenylacetylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl-3-(2-methoxyphenylacetylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(2,3-dimethoxyphenylacetylamino)-4-(4pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(2,3-methylenedioxyphenylacetylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(4-hydroxyphenylacetylamino)-4-(4-pyridyl)pyrazole,
3-(4-aminophenylacetylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(4-dimethylamminophenylacetylamino)-4-(4-pyridyl)pyrazole,
3-(4-acetylaminophenylacetylamino)-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(2-bromo-4-fluorophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-chloro-2-fluorophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chloro-4-methylphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chloro-4-methoxyphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chloro-4-trifluromethylphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chloro-4-hydroxyphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-amino-2-chlorophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chloro-4-nitrophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-ethylphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2,4-ditrifluromethylphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(2-hydroxyphenylacetylamino)-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-acetoxyphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(4-mercaptophenylacetylamino)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(2-methylthiophenylacetylamino)-4-(4-pyridyl)pyrazole,
5-(4-dimethylaminophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-acetylaminophenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(L-tyrosylamino)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(2-pyridylacetylamino)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(2-quinolylacetylamino)pyrazole,
5-(4-fluorophenyl)-3-(3-piperidinopropionylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(L-tryptophylamino)pyrazole,
3-cyclohexylcarbonylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(4-hydroxycyclohexylcarbonylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(4-pyridylcarbonylamino)pyrazole,
5-(4-fluorophenyl)-3-(3-furoylamino)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(2-thenoylamino)pyrazole,
5-(4-fluorophenyl)-4-(4-pyridyl)-3-(2-quinolylcarbonylamino)pyrazole,
5-(4-fluorophenyl)-3-(4-methylpiperazinylcarbonylamino)-4-(4-pyridyl)pyrazole,
5-(3-chloro-4-fluorophenyl)-3-phenylacetylamino-4-(4-pyridyl)pyrazole,
3-(3-chloro-4-fluorophenyl)-5-(2-chlorophenylacetylamino)-1-methyl-4-(4-pyridyl)pyrazole,
5-(3-chloro-4-fluorophenyl)-3-(2-phenylpropionylamino)-4-(4-pyridyl)pyrazole,
3-methoxalylamino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-phenyloxalylamino-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-[phenyl(thioacetyl)amino]-4-(4-pyridyl)pyrazole,
5-(4-fluorophenyl)-3-(2-phenylpropionylamino)-4-(4-quinolyl)pyrazole,
3-(4-chlorophenylacetylamino)-5-(4-fluorophenyl)-4-(4-quinolyl)pyrazole,
3-(4-fluorophenyl)-5-[N-(2-fluorophenylacetyl)-N-methylamino]-1-methyl-4-(4-pyridyl)pyrazole,
5-[N-(2-bromophenylacetyl)-N-methylamino]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-[N-(2-chloro-4-fluorophenylacetyl)-N-methylamino]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-[N-(2,5-difluorophenylacetyl)-N-methylamino]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(N-ethyl-N-phenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
1-ethyl-5-(N-ethyl-N-phenylacetylamino)-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
1-(2-hydroxyethyl)-5-[N-(2-hydroxyethyl)-N-phenylacetyl-amino]-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-(N-benzyl-N-phenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-[N-(4-chlorophenylmethyl)-N-phenylacetylamino]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in accordance with the present invention can form salts. Examples of such salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and salts formed with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid. Among others, pharmaceutically acceptable salts are preferred.
According to the present invention, depending on the types of the substituents represented by R1, R2 and R3, the compounds of the above formula (1) may be prepared, for example, by any of the processes (a) to (e) described below.
Process (a): The compounds of the above formula (I) in which R2 is a hydrogen atom, R3 is xe2x80x94C(xe2x95x90Y)xe2x80x94R4, and Y is an oxygen atom may be prepared by:
(i) reacting an amino compound of the formula 
xe2x80x83wherein X1, X2, Q and R1 have the above-defined meanings, with a carboxylic acid of the formula
R4xe2x80x94COOHxe2x80x83xe2x80x83(II)
xe2x80x83wherein R4 has the above-defined meaning, or a reactive derivative thereof; or
(ii) reacting a reactive derivative of an amino compound of the above formula (II) with a carboxylic acid of the above formula (III).
Process (b): The compounds of the above formula (I) in which R3 is xe2x80x94C(xe2x95x90Y)xe2x80x94R4 and Y is a sulfur atom may be prepared by treating a compound of formula (I) in which Y is an oxygen atom, with the Lawesson reagent.
Process (c): The compounds of the above formula (I) in which R2 is a hydrogen atom and R3 is an organic sulfonyl group may be prepared by treating a compound of the above formula (II) with an organic sulfonic acid or a reactive derivative thereof.
Process (d): The compounds of the above formula (I) in which R1 is a substituted or unsubstituted lower alkyl group may be prepared by alkylating a compound of formula (I) in which R1 is a hydrogen atom, for example, by treating it with a substituted or unsubstituted lower alkyl halide.
Process (e): The compounds of the above formula (I) in which R2 is a lower alkyl group or an aralkyl group having an optionally substituted aryl moiety may be prepared by alkylating or aralkylating a compound of formula (I) in which R2 is a hydrogen atom, for example, by treating it with a lower alkyl halide or an aralkyl halide.
In the above-described process (a) (i), the reaction of the amino compound of formula (II) with the carboxylic acid of formula (III) or its reactive derivative (e.g., acid chloride, acid anhydride, mixed acid anhydride, activated amide or activated ester) may generally be carried out in an inert organic solvent selected, for example, from ethers such as dioxane, tetrahydrofuran and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethylacetamide; and dimethyl sulfoxide. If necessary, this reaction may also be carried out in the presence of a base such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine or N-methylmorpholine. The reaction temperature may vary according to the type of the carboxylic acid of formula (II) or its reactive derivative used. However, it is usually suitable to employ a temperature ranging from xe2x88x9210xc2x0 C. to the reflux temperature of the reaction mixture and preferably from an ice-cold temperature to about 50xc2x0 C.
In the above-described process (a) (i), when a free carboxylic acid is used as the carboxylic acid of formula (III), it is preferable to treat the carboxylic acid, for example, with 1,1-carbonyldiimizadole or 1,1-thionyldiimizadole in advance and thereby convert it to a reactive derivative (e.g., imidazolide).
When an acid chloride is used as the reactive derivative, it is possible to treat the acid chloride, for example, with imidazole or DBU in advance, and thereby convert it to another reactive derivative (e.g., imidazolide) prior to reaction.
When an acid chloride or a mixed acid anhydride is used as the reactive derivative, not only a carboxylic residue is introduced into the desired amino group at the 3-position of the pyrazole ring, but also another carboxylic residue may be introduced at one of the nitrogen atoms constituting the pyrazole ring and/or (where Q is a 4-pyridyl group) at the nitrogen atom of the 4-pyridyl group. Such a compound having a plurality of carboxylic residues introduced thereinto can be converted to a compound of formula (I) in accordance with the present invention by subsequent treatment with an alkali such as sodium hydroxide or potassium hydroxide.
In the above-described process (a) (i), the proportion of the carboxylic acid of formula (III) or its reactive derivative to the compound of formula (II) may generally be such that the carboxylic acid of formula (III) or its reactive derivative is used in an amount of at least 1 mole, preferably 1.5 to 10 moles, and more preferably 2 to 5 moles, per mole of the compound of formula (II). The base may generally be used in an amount of at least 1 mole and preferably 1 to 2 moles, per mole of the carboxylic acid of formula (III) or its reactive derivative.
In the above-described process (a) (ii), the reaction of the reactive derivative (e.g., phosphazo compound, phosphoroamidate compound, phosphoroamidide compound, isocyanate or thioisocyanate) of the amino compound of formula (II) with the carboxylic acid of formula (III) may generally be carried out in an inert organic solvent selected, for example, from ethers such as dioxane, tetrahydrofuran and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethylacetamide; and dimethyl sulfoxide. If necessary, this reaction may also be carried out in the presence of a base such as pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene ()BU), triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine or N-methylmorpholine. The reaction temperature may vary according to the type of the reactive derivative of the amino compound of formula (II) used. However, it is usually suitable to employ a temperature ranging from xe2x88x9210xc2x0 C. to the reflux temperature of the reaction mixture and preferably from an ice-cold temperature to about 50xc2x0 C.
The above-described reaction may usually be carried out by treating a free amino compound of formula (II) with phosphorus trichloride, tetraethyl pyrophosphate, phosgene or the like in the presence of the above-described base, and reacting the resulting Nu reactive derivative of the amino compound of formula (II) with a carboxylic acid of formula (III) without isolating the reactive derivative.
In the above-described process (b), the treatment with the Lawesson reagent of the compound of formula (I) in which Y is an oxygen atom may generally be carried out in an inert organic solvent such as an aromatic hydrocarbon (e.g., benzene, toluene or xylene). As the reaction temperature, it is usually suitable to employ a temperature ranging from 50xc2x0 C. to the reflux temperature of the reaction mixture and preferably from 80xc2x0 C. to the reflux temperature of the reaction mixture.
The Lawesson reagent used in process (b) is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. This Lawesson reagent may generally be used in an amount of at least 1 mole and preferably 1.05 to 1.5 moles, per mole of the compound of formula (I) in which Y is an oxygen atom.
The treatment with the organic sulfonic acid or its reactive derivative (e.g., acid chloride) in the above-described process (c) may generally be carried out in an inert organic solvent selected, for example, from ethers such as dioxane, tetrahydrofuran and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethylacetamide; and dimethyl sulfoxide. As the reaction temperature, it is usually suitable to employ a temperature ranging from 0xc2x0 C. to the reflux temperature of the reaction mixture and preferably from an ice-cold temperature to the vicinity of room temperature.
It is preferable to treat the compound of formula (II) with a base (e.g., sodium hydride, sodium amide or potassium t-butoxide) in advance and thereby activate its amino group.
In process (c), the proportion of the organic sulfonic acid or its reactive derivative to the compound of formula (II) may generally be such that the organic sulfonic acid or its reactive derivative is used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1.05 to 1.5 moles, per mole of the compound of formula (II).
In the above-described process (d), the treatment with a lower alkyl halide of the compound of formula (I) in which R1 is a hydrogen atom may generally be carried out in an inert organic solvent selected, for example, from ethers such as dioxane, tetrahydrofuran and dimethoxyethane; amides such as dimethylformamide and dimethylacetamide; and aromatic hydrocarbons such as benzene and toluene, and in the presence of a base such as sodium hydride, sodium amide, potassium t-butoxide, potassium carbonate or sodium carbonate. The lower alkyl halides which can be used in this treatment include, for example, methyl iodide, ethyl iodide and isopropyl iodide. As the reaction temperature, it is usually suitable to employ a temperature ranging from 0xc2x0 C. to the reflux temperature of the reaction mixture and preferably from an ice-cold temperature to the vicinity of room temperature.
The proportion of the lower alkyl halide to the compound of formula (I) in which R1 is a hydrogen atom may generally be such that the lower alkyl halide is used in an amount of at least 1 mole and preferably 1.1 to 1.5 moles, per mole of the compound of formula (I).
In the above-described process (e), the treatment with a lower alkyl halide of the compound of formula (I) in which R2 is a hydrogen atom may be carried out in the same manner as described above for process (d) involving the treatment with a lower alkyl halide of the compound of formula (I) in which R1 is a hydrogen atom. Moreover, the treatment with an aralkyl halide (e.g., benzyl bromide or phenetyl iodide) of the compound of formula (I) in which R2 is a hydrogen atom may be carried out under substantially the same reaction conditions as described above for process (d) involving the treatment with a lower alkyl halide of the compound of formula (I) in which R1 is a hydrogen atom.
Where this reaction is carried out by using a compound of formula (I) in which both R1 and R2 are hydrogen atoms, it is advantageous to protect the nitrogen atoms of the pyrazole ring with protecting groups (e.g., pyrrolidine) in advance and eliminating the protecting groups after completion of the reaction.
In the reactions described herein, when the group represented by R3 contains a group which may participate in the reaction (e.g., amino, hydroxyl or carboxyl), it is advantageous to protect this group suitably with an appropriate protecting group (e.g., benzyloxycarbonyl or t-butoxycarbonyl for amino; benzyl acetyl or methoxymethyl for hydroxyl; methyl ester or ethyl ester for carboxyl) in advance and eliminating the protecting groups after completion of the reaction.
The compounds of the above formula (I) or their salts, which have been formed in the above-described manner, may be isolated and purified from the reaction mixture by per se known techniques such as recrystallization, distillation, column chromatography and thin-layer chromatography.
The aminopyrazole derivatives of formula (I) or their salts in accordance with the present invention, which have been described above, have excellent p38MAP kinase inhibiting activities and are hence effective in hindering the production of TNF-xcex1, IL-1, IL-6, COX-II and the like. Accordingly, they are useful as agents for the treatment of diseases associated with TNF-xcex1, IL-1, IL-6 or COX-II, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, viral and bacterial infections, asthma, septic shock, IBD, Crohn""s disease, Alzheimer""s disease, diabetes, cachexia, osteoporosis, graft versus host disease, adult RDS, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, SLE, thrombosis, born resorption disease, chronic pulmonary inflammation disease, cardiac reperfuision injury, renal reperfusion injury, cancer, Reiter""s syndrome, preterm labor, eczema, allograft rejection, stroke, fever, Behqet""s disease, neuralgia, meningitis, sunburn, contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, pancreatitis, glioblastoma, bleeding, joint inflammation, endotoxic shock, parasitic infections, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, IBS, transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling, low back pain, laryngopharyngitis, Kawasaki disease, myelopathy and atopic dermatitis.
The p38MAP kinase (p38MAPK) inhibiting activities of the compounds of formula (I) or their salts in accordance with the present invention can be measured in the following manner.
(1) Measurement of Inhibitory Activities against the Binding of p38MAPK
Inhibitory activities against the binding of p38MAPK were measured by use of the cytosol fraction of THP-1 cells which are cultured cells derived from the human monocyte. Specifically, THP-1 cells were suspended in a cell lysis buffer [20 mM Tris-HCl buffer (pH 7.4), 1 mM magnesium chloride, 1 mM PMSF (phenylmethylsulfonyl fluoride), 1 mM pepstatin A, 1 mM leupeptin, 10 mg/ml aprotinin] and then ultrasonicated in water. Thereafter, the suspension was centrifuged at 100,000xc3x97g for 1 hour, and the protein concentration of the resulting supernatant (cytosol fraction) was determined. This supernatant was diluted with the cell lysis buffer so that the protein concentration of the cytosol fraction was 1 mg/ml, dispensed, and stored at xe2x88x9280xc2x0 C. till use.
The inhibitory activity of a test compound against the binding of p38MAPK was measured by incubating a mixture of the cytosol fraction (100 xcexcg protein) of THP-1 cells and the test compound at 15xc2x0 C. for 30 minutes, adding thereto 1.11 KBq of 3H-SB202190 (925 GBq/mmol; manufactured by Americium, England) as a radioligand, and reacting the resulting mixture at 15xc2x0 C. for 3 hours. Nonspecific binding was measured by adding 20 xcexcM SB203580. In order to separate the free and bound types of radioligand, a charcoal solution (1% charcoal, 0.1% dextran T-70). The resulting mixture was cooled with ice for 15 minutes and then centrifuged (3,000 rpm, 10 minutes, 4xc2x0 C.). After the addition of a liquid centiliter to the resulting supernatant, its radioactivity was measured with a liquid scintillation counter.
3H-SB202190 used as a radioligand was 4-(4-fluorophenyl)-2-(4-hydroxy-3,5-di-3H-phenyl)-5-(4-pyridyl)imidazole, and SB203580 added for the measurement of nonspecific binding was 4-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-5-(4-pyridyl)imidazole.
The results of measurement of compounds in accordance with the present invention are given below.
As described above, the compounds of the above formula (I) or salts thereof in accordance with the present invention have an excellent inhibitory activity against the binding of p38MAPK, and can hence be used as p38MAP kinase inhibitors for purposes of prophylaxis, therapy and treatment in human beings and other mammals by oral administration or parenteral administration (e.g., intramuscular injection, intravenous injection, intraarticular administration, intrarectal administration or percutaneous administration).
When the compounds of the present invention are used as drugs, they may be formed into any of various pharmaceutical preparations according to the intended purpose. These pharmaceutical preparations include solid preparations (e.g., tablets, hard capsules, soft capsules, granules, powders, fine subtilaes, pills, troches and patches), semisolid preparations (e.g., suppositories and ointments), and liquid preparations (e.g., injections, emulsions, suspensions, lotions and sprays). Nontoxic additives which can be used in the aforesaid pharmaceutical preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose and salts thereof, acacia, polyethylene glycol, alkyl esters of p-hydroxybenzoic acid, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate and citric acid. The aforesaid pharmaceutical preparations may also contain other therapeutically useful drugs.
The content of the compounds of the present invention in the aforesaid pharmaceutical preparations may vary according to the dosage form. Generally, it is desirable that solid and semisolid preparations contain the compounds of the present invention at a concentration of 0.1 to 50% by weight and liquid preparations contain them at a concentration of 0.05 to 10% by weight.
The dosage of the compounds of the present invention may vary widely according to the type of the mammal (including human being) to be treated, the route of administration, the severity of symptoms, the doctor""s diagnosis, and the like. Generally, they may be administered in a daily dose of 0.02 to 10 mg/kg and preferably 0.1 to 2 mg/kg. However, it is a matter of course that they may be administered in doses less than the lower limit of the aforesaid range or greater than the upper limit thereof, depending on the severity of symptoms in the patient and the doctor""s diagnosis. The aforesaid daily dose may be given at a time or in several divided doses.